Small leucine-rich proteoglycans in atherosclerotic lesions: novel targets of chronic statin treatment?

Abstract

Small leucine-rich proteoglycans (SLRPs), such as decorin and biglycan, regulate the assembly and turnover of collagenous matrix. The aim of the study was to analyse the effect of chronic rosuvastatin treatment on decorin, biglycan and the collagen matrix in ApoE-deficient mice. Twenty-week-old male ApoE-deficient mice received normal chow or 20 mg rosuvastatin/kg × day for 32 weeks. Subsequently, matrix composition was analysed by histochemistry and immunostaining at the aortic root and in innominate arteries of ApoE deficient mice as well as in human carotid endarterectomy specimens. Immunoblotting of proteoglycans was performed from aortic extracts of ApoE-deficient mice. Immunohistochemistry and immunoblotting revealed strongly increased decorin and biglycan deposition in atherosclerotic plaques at the aortic root and in innominate arteries. In contrast, versican and perlecan expression was not changed by rosu-vastatin. Furthermore, matrix metalloproteinase 2 and gelatinolytic activity were decreased in response to rosuvastatin and a condensed collagen-rich matrix was formed. In carotid endarterectomy specimens of statin-treated patients increased decorin and biglycan accumulation was detected as well. Drug treatment did not change low-density lipoprotein (LDL) plasma levels in ApoE-deficient mice and did not significantly affect lipid retention at the aortic root level as demonstrated by oil-red O staining and immunohistochemistry of LDL. Long-term treatment with rosuvastatin caused pronounced remodelling of atherosclerotic plaque matrix characterized specifically by enrichment with SLRPs and formation of a condensed collagen matrix. Therefore, decorin and biglycan might represent novel targets of statin treatment that contribute to a stable plaque phenotype.

Deficiency of Biglycan Causes Cardiac Fibroblasts to Differentiate into a Myofibroblast Phenotype

“…Together these two mechanisms may cause decreased stability and increased tension and therefore increased susceptibility of the scar to rupture. The function of bgn during fibroblast phenotype regulation might also be important to consider in response to various pharmacologic treatments that affect bgn expression and deposition such, as angiotensin II receptor type 1 antagonists or statins (66,67).…”

The multifaceted roles of perlecan in fibrosis

“…Statins are effective in lowering LDL cholesterol [210] and also reduced plaque volume when used at high dose [210]. ApoE deficient mice treated with statins also display reduced plaque volume with increased decorin and biglycan expression and a more condensed collagen rich ECM, however perlecan expression was not altered in these mice [211] even though it has a major role in LDL retention and has been shown to modulate HS proteoglycan expression [35]. The renin-angiotensin system (RAS) is a central regulatory system for cardiovascular function and critically connected to atherosclerosis and mediated by angiotensin II.…”

Loss of Biglycan Enhances Thrombin Generation in Apolipoprotein E -Deficient Mice

“…23,24 Furthermore, biglycan content is regulated by statins, angiotensin type 1 receptor antagonists, and likely other drugs that are regularly used to treat patients at high risk of cardiovascular events. 18,25,26 No previous studies have addressed the question whether biglycan circulates in patients with coronary heart disease or in ApoE −/− mice. Interestingly, the current study found that circulating concentrations of biglycan are increased in ApoE −/− mice and in patients with acute coronary syndrome.…”

“…The conclusion that the absence of biglycan does not crucially affect lipoprotein retention in atherosclerotic plaques is also supported by the observation that chronic treatment with statins dramatically increases the concentrations of biglycan in atherosclerotic plaques without affecting the retention of lipoproteins in late atherosclerosis. 18 Comparing human atherosclerosis-prone internal carotid arteries with atherosclerosis-resistant internal thoracic arteries found no difference in biglycan content. 42 However, the current findings do not rule out the possibility that biglycan contributes to the subendothelial accumulation of lipoprotein during early intimal thickening in humans because biglycan is expressed at sites of subsequent lipid deposition and macrophage accumulation.…”

“…In this study, it is considered that gagylated biglycan might serve as an inhibitor of thrombin activity in ApoE-deficient mice. In atherosclerosis, expression of biglycan has been demonstrated in atherosclerotic plaques 12,18 where it may confer local inhibition of thrombin. Here, it was investigated whether biglycan (1) circulates, (2) is present in the glycocalyx, and (3) is deposited in the subendothelial matrix.…”